Nitric oxide is a gas. It is highly reactive; that is, it participates in many chemical reactions. (It is one of the nitrogen oxides ("NOx") in automobile exhaust and plays a major role in the formation of photochemical smog [Link].)

eNOS (or NOS-3): found in the endothelial (hence the "e") cells that line the lumen of blood vessels.

iNOS (or NOS-2): found in macrophages. (the "i" stands for "inducible"). Whereas the levels of nNOS and eNOS are relatively steady, expression of iNOS genes awaits an appropriate stimulus (e.g., invasion by a pathogen).

All types of NOS produce NO from arginine with the aid of molecular oxygen and NADPH.

NO diffuses freely across cell membranes.

There are so many other molecules with which it can interact, that it is quickly consumed close to where it is synthesized.

Thus NO acts in a paracrine or even autocrine fashion — affecting only cells near its point of synthesis.

NO relaxes the smooth muscle in the walls of the arterioles. At each systole, the endothelial cells that line the blood vessels release a puff of NO. This diffuses into the underlying smooth muscle cells causing them to relax and thus permit the surge of blood to pass through easily. Mice whose genes for the NO synthase found in endothelial cells (eNOS) has been "knocked out" suffer from hypertension.

Nitroglycerine, which is often prescribed to reduce the pain of angina, does so by generating nitric oxide, which relaxes the walls of the coronary arteries and arterioles.

Three of the pioneers in working out the biological roles of NO shared a Nobel Prize in 1998 for their discoveries. The award to one of them, Ferid Murad, honored his discovery that nitroglycerine works by releasing NO. This seems particularly appropriate because Alfred Nobel's fortune came from his invention of making dynamite from nitroglycerine!

The erection of the penis during sexual excitation is mediated by NO released from nerve endings close to the blood vessels of the penis. Relaxation of these vessels causes blood to pool in the blood sinuses producing an erection.

Recent evidence suggests that NO's job in reproduction is not finished with producing an erection. At the moment of contact, release of NO by the acrosome of the sperm activates the egg to complete meiosis II and the other steps of fertilization.

Some motor neurons of the parasympathetic branch of the autonomic nervous system release NO as their neurotransmitter. The actions of NO on penile erection and peristalsis are probably mediated by these nerves.

The acrosome at the tip of sperm heads activates its NO synthase when it enters the egg. The resulting release of NO in the egg is essential (at least in sea urchins) for triggering the next steps in the process :

Mice whose genes for the NO synthase found in macrophages (iNOS) have been knocked out are more susceptible to infections by intracellular bacteria like Listeria monocytogenes.

Th1 cells, the ones responsible for an inflammatory response against invaders, secrete NO.

Harmless bacteria, living as commensals at the rear of our throat, convert nitrates in our food into nitrites. When these reach the stomach, the acidic gastric juice (pH ~1.4) generates NO from them. This NO kills almost all the bacteria that have been swallowed in our food.

(Since the dawn of recorded human history, nitrites have been used to preserve meat from bacterial spoilage.)

In either case, binding triggers an allosteric change in the protein which, in turn, triggers the formation of a "second messenger" within the cell. The most common protein target for NO seems to be guanylyl cyclase, the enzyme that generates the second messenger cyclic GMP (cGMP).

Three prescription drugs

sildenafil (Viagra®)

vardenafil (Levitra®)

tadalafil (Cialis®)

enhance the effects of NO by inhibiting the enzyme that normally breaks down cGMP.

It is a weapon against invading pathogens. Infection of the plant triggers the formation of a NOS that, like the animal versions, makes NO from arginine. Release of NO by the infected cell induces a number of defense responses.

A gradient of NO may also guide the pollen tube to its destination in the ovule [Link]. The popular prescription drug sildenafil citrate (Viagra®) enhances the effect of NO on pollination (just as it does on penile erection).